NW Symposium in Melanoma
May 22, 2010
Adoptive T Cell Therapy
Cassian Yee MD
Member
Program in Immunology
Fred Hutchinson Cancer Research Center
cyee@fhcrc.org
T Cell
Melanoma Cell
Melanoma Cell
T Cell
Tumor Cell
T Cell
TCR
Target Antigen
An tige n
Differentiation Antigens (overexpres
sed)
T yrosinase
MART 1/MelanA
gp100
Differentiation Antigens (norm ally expr.)
P rostate specific an
tigens
CD20, Idiotype
Cancer-Testis Antigens
MAGE-1, MAGE-3
NY-ESO-1
Oncofetal Antigens
CEA
AFP
Viral Antigens
EBV
Mutated Antigens
CASP-8
CDK4-kinase, MUM-3
Beta-catenin
Minor Histocom patibility An
tigens
HA-1, HA-2
Tissu e Expression
T umors
Normal T issues
Melanoma
Melanoma
Melanoma
Melanocytes
Melanocytes
Melanocytes
P rostate Cancer
B cell malignancies
P rostate
B cells
Melanoma, Lung,Others
Breast, Ovarian,Lung,
Melanoma, Others
T estis, P lacenta
T estis, P lacenta
Colon Cancer, Others
Liver Cancer
Liver, Others
NP C, Hodkgin’s, LP D
Head and Neck Cancer
Melanoma
Melanoma, Lung,Others
-
Leukemia, RCC, Breast
*allogeneic
WBCs
B cells
RBCs
platelets
WBCs
T cells
Tumor Cell
T Cell
CD8+
TCR
1 in 100,000
Target Antigen
Tumor Immune Surveillance
Tumor
Normal
CD4
CD8
DC
DC
DC
DC
Possible Reasons For Failure of
Tumor Immune Surveillance
Highly
functional
• Immune
evasion T cells
• T cell
More
offrequency
them : Tumor burden
Vaccine Therapy
Adoptive Therapy
Adoptive T Cell Therapy
Tumor
CD4
CD8
DC
DC
DC
DC
LEUKAPHERESIS
WBCs
Study in Patients with Advanced
Melanoma
Treated with T Cell Therapy
Recruited patients with

metastatic disease

progressive

failing 2nd and 3rd attempts to treat cancer
Before
Patient 1017-6
Patient 1017-8
After T cell infusion
Study in Patients with Advanced
Melanoma
Treated with T Cell Therapy
•
•
•
•
30% Failed
30% Partial Response
30% Stabilized Response
10% near Complete Response
3 to > 30 months
Lymphoid Homeostasis
20
Lymphodepletion
building a better environment
Increase 'space' for transferred T cells
Eliminate 'suppressor cells'
Supply Growth Factors
PROTOCOL # 2140
Adoptive T Cell Therapy following Cyclophosphamide Lymphodepletion
Objectives :
- Evaluate Safety
- Evaluate T Cell Persistence
- Evaluate anti-tumor efficacy
Eligibility Criteria :
- Stage IV (Metastatic)
- HLA-A2
T Cell Infusion:
- Antigen-specific CD8+ T cell clones
- Targeting MART-1, gp100
- Dose: 1010 cells / m2
CY
60 mg/kg x 2
Low-Dose IL-2 (250,000 U s.c q12 h)
T cell persistence in vivo
250000
2140-1
200000
150000
9.4%
100000
5.3%
50000
1.1%
0
0
D18
50
100
150
200
250
200
250
300
Days post Infusion
5000
2140-2
CTL frequency/10^6
4000
3000
2000
1000
0
0
50
100
150
Days post Infusion
300
Clinical Response
Patient
Target
Toxicity
Persistence
Disease Sites
Response
2140-1
Tyrosinase
F,N,R
>290 days
Cervical,supraclavicular LN,
Chest Wall, Breast
Pulmonary nodules
MR
2140-2
Tyrosinase
F
16 days
Mediastinal, Pulmonary nodules
PD
2140-3
gp100
F,N,R
>85 days
Mesenteric LN, scapular
subcutaneous dz
CR (> 12 mths)
2140-4
MART-1
F, N, R
n.d.
Pulmonary, inguinal,
subcutaneous
SD
2140-5
MART-1
F, N,R
n.d.
Right and left kidneys, adrenal,
liver
PR
2140-6
MART-1
F, N, R
n.d.
Mediastinal, supra clavicular,
mammary chain, periportal,
portacaval nodes.
PR
Future Directions
Future of
Adoptive T Cell Therapy
•
•
•
•
LATE-STAGE DISEASE
EARLY-STAGE DISEASE
COMBINATION THERAPY
WHICH CANCER TYPES?
An tige n
Differentiation Antigens (overexpres
sed)
T yrosinase
MART 1/MelanA
gp100
Differentiation Antigens (norm ally expr.)
P rostate specific an
tigens
CD20, Idiotype
Cancer-Testis Antigens
MAGE-1, MAGE-3
NY-ESO-1
Oncofetal Antigens
CEA
AFP
Viral Antigens
EBV
Mutated Antigens
CASP-8
CDK4-kinase, MUM-3
Beta-catenin
Minor Histocom patibility An
tigens
HA-1, HA-2
Tissu e Expression
T umors
Normal T issues
Melanoma
Melanoma
Melanoma
Melanocytes
Melanocytes
Melanocytes
P rostate Cancer
B cell malignancies
P rostate
B cells
Melanoma, Lung,Others
Breast, Ovarian,Lung,
Melanoma, Others
T estis, P lacenta
T estis, P lacenta
Colon Cancer, Others
Liver Cancer
Liver, Others
NP C, Hodkgin’s, LP D
Head and Neck Cancer
Melanoma
Melanoma, Lung,Others
-
Leukemia, RCC, Breast
*allogeneic
An tige n
Differentiation Antigens (overexpres
sed)
T yrosinase
MART 1/MelanA
gp100
Differentiation Antigens (norm ally expr.)
P rostate specific an
tigens
CD20, Idiotype
Cancer-Testis Antigens
MAGE-1, MAGE-3
NY-ESO-1
Oncofetal Antigens
CEA
AFP
Viral Antigens
EBV
Mutated Antigens
CASP-8
CDK4-kinase, MUM-3
Beta-catenin
Minor Histocom patibility An
tigens
HA-1, HA-2
31
Tissu e Expression
T umors
Normal T issues
Melanoma
Melanoma
Melanoma
Melanocytes
Melanocytes
Melanocytes
P rostate Cancer
B cell malignancies
P rostate
B cells
Melanoma, Lung,Others
Breast, Ovarian,Lung,
Melanoma, Others
T estis, P lacenta
T estis, P lacenta
Colon Cancer, Others
Liver Cancer
Liver, Others
NP C, Hodkgin’s, LP D
Head and Neck Cancer
Melanoma
Melanoma, Lung,Others
-
Leukemia, RCC, Breast
*allogeneic
Adoptive Therapy following Lymphodepletion
TBI
FLU
CY
60 mg/kg x 2 25 mg/m2 x
5
HD IL-2
720K u/kg TID
Low-Dose
s.c q12
High-DoseIL-2
IL-2(250,000
(600,000Uu./kg
q8)h)
Adoptive Therapy following Cytoxan Lymphodepletion
Protocol 2140
CY
60 mg/kg x 2
HD IL-2
720K u/kg TID
Low-Dose
s.c q12
High-DoseIL-2
IL-2(250,000
(600,000Uu./kg
q8)h)
Translational Strategies to Augment the CD8 Effector Response
Ê
Isolate/Enrich
 Cytokine modulation
CD4
Genetically Modify




TCR
Chimeric receptor
Costimulatory/Inhbitory modification
Suicide gene
Tet-PE
Intrinsic
Clone/Select
 Phenotype
- CD8/CD4
- Memory phenotype
CD8-FITC
Expand
Extrinsic
Pre-infusion
Immunomodulation
 Lymphodepletion
- Chemotherapy/TBI
Fludarabine
Post-infusion
Immunomodulation
 Cytokine help
- Low-dose IL-2
- High-dose IL-2
- Other -chain receptor cytokines
 Vaccine + adoptive therapy
Hematol Oncol Clin North Am. 2006 Jun;20(3):711-3
Adoptive Therapy Using Antigen-Specific T cells
Transferred Receptor
Tumor Cell
Chimeric
TCR + zeta
Chimeric
Ig + zeta
Receptor Transfer
T Cell Expansion & Infusion